RANK pathway inhibition sensitizes triple-negative breast cancer to CDK4/6 inhibitors and enhances immune response

Despite chemotherapy's limitations and toxic effects, it remains the primary treatment for most triple-negative breast cancer (TNBC) patients. While cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy have revolutionized luminal breast cancer treatment, CDK4/6i alone are largely ineffective in TNBC, even with functional retinoblastoma protein (pRB). The receptor activator of nuclear factor-κB (RANK) pathway has been linked to poor prognosis in TNBC. Previous research connected RANK with resistance to CDK4/6i in luminal breast cancer, which could be reversed by RANK ligand inhibitors (RANKLi). In this study, RANK knockdown or RANKLi treatment sensitized pRB-proficient TNBC cells to CDK4/6i, reducing tumor growth and metastasis. Combining CDK4/6i with RANKLi enhanced cell cycle arrest and elicited an immune response in the tumor microenvironment across BC subtypes. These findings suggest that combining CDK4/6i and RANKLi is a promising therapeutic approach for pRB-proficient TNBC, with potential immunomodulatory benefits, warranting further investigation.